Mechanisms underlying myocardial ischemia and reperfusion injury (also referenced as “I/R” injury) were extensively studied but are, unfortunately, neither completely known nor completely explained and understood today.
Respective pathogenesis was demonstrated to at least include inflammation, endothelial dysfunction, mitochondrial damage, cardio myocyte apoptosis and necrosis as well as involvement of reactive oxygen species. For example, the production of cytokines seems to play an important role in producing and developing acute myocardial ischemia. Within hours after the blood reflow to ischemic myocardium, cytokines seems to be secreted locally. Furthermore, inflammatory mediators are expected to be released which aggravates a possible reperfusion injury of myocardial cells. During I/R, inflammatory cytokines might modulate myocardial survival by various mechanisms including stimulation of hypertrophy and fibrosis, impairment of myocardial contractile function, induction of apoptosis and stimulation of genes involved in myocardial remodeling. Pro-inflammatory cytokines such as TNF-α (Tumor necrosis factor alpha) and IL-6 (Interleukin 6) are commonly used biomarkers contribute to up-regulation of cell-adhesion molecules, cardiac functional depression and myocardial damage. After myocardial ischemia, NF-κB (Nuclear factor kappa B) was reported to have either cardioprotective or cardiotoxic effects. Prolonged activation of NF-κB appeared to be cardiotoxic in heart failure by inducing signaling cascades triggering chronic inflammation. Inhibition of NF-κB activation was demonstrated to be less susceptible to I/R. In this context, injury was more dominant from reperfusion than that from ischemia and release of inflammatory substances was thought to be one important cause of reperfusion-associated pathologies, such as cardiomyocyte death, contraction band necrosis, reduced reflow and ventricular arrhythmia.
Experimental studies in animals indicated that therapeutic interventions for example with anti-inflammatory compounds might contribute to a reduction of infarct size and attenuation of cardiac dysfunction. And after myocardial infarction occurred, restoration of blood flow was considered for being the best effective way to save the myocardium from ischemic damage. However, predicting when myocardial infarction occurs and preventing the infarction with long-time use of such compounds is usually not a practical and convenient way for successfully treating infarction.
There is still a need for therapeutically effective compounds and, thus, improved ways for successfully treating I/R injuries, especially myocardial ischemia reperfusion injuries. As usual, it is generally desirable to have compounds with reduced risk for side effects, which can be prepared in a cost-effective way.
Traditional Chinese medicines based on plant materials as well as plants or respective components gained from plants usually allow for treatment of various diseases and conditions while bearing a reduced risk for side effects. In view of the rich medicinal plant resources available respective medicines can usually be produced in a cost-effective way. Accordingly, there has been a lot of research with regard to plants and respective ingredients for treatment of several diseases and conditions.
For example, Erigeron multiradiatus (Lindl.) Benth, is a biennial or perennial herb and distributed mainly in the Qinhai-Tibet plateau of China at altitudes ranging from 2600 to 4300 meters. In traditional Tibetan medicine, E. multiradiatus has been used for years for the treatment of diseases including hypopepsia, enteritis, diarrhea, food poisoning as well as fever and cough. Studies of phytochemistry reported that flavonoids, phenolic acids and sterols are presented abundantly in this plant. The phenolic acids of E. multiradiatus were under investigation, both in phytochemical and bioactive studies. It has been reported that usual or crude extracts of this plant with increased content of flavonoids may have several pharmacological effects including anti-inflammatory ones (e.g. Luo, P. et al., J Ethnopharmacol, 2008, 119:232-237).
The inventors unexpectedly found that a caffeoylquinic acid-rich extract obtained from this plant comprising a mixture of certain caffeoylquinic acids namely a mixture of certain dicaffeoylquinic acids, tricaffeoylquinic acids and Erigoster-based ones proved to be exceptionally efficacious and, thus, provides a highly promising treatment option for treatment of I/R injuries. While several phytochemical and pharmacological aspects of some caffeoylquinic acids isolated from other plants than E. multiradiatus or synthetic ones have been provided and respective effects have been evaluated so far (dos Santos et al., Nat Prod Commun, 2010, 5:733-740, Han et al., Neuroscience, 2010, 169:1039-1045, dos Santos et al., Eur J Pharm Sci, 2005, 26: 62-70, Chiou et al., Evid Based Complement Alternat Med, 2011, 634502, doi: 10.1093/ecam/nep140. Epub 2011 Jun. 18), such evaluation did not focus on possible effects of caffeoylquinic acids in E. multiradiatus, and, hence, of those caffeoylquinic acids on I/R injuries.